Fluorine Scanning by Nonselective Fluorination: Enhancing Raf/MEK Inhibition while Keeping Physicochemical Properties

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A systematic RNAi screen reveals involvement of endocytic pathway in neuronal dysfunction in alpha-synuclein transgenic C. elegans

Mutations or multiplications in alpha-synuclein gene cause familial forms of Parkinson disease or dementia with Lewy bodies (LB), and the deposition of wild-type alpha-synuclein as LB occurs as a hallmark lesion of these disorders, collectively referred to as synucleinopathies, implicating alpha-synuclein in the pathogenesis of synucleinopathy. To identify modifier genes of alpha-synuclein-induced neurotoxicity, we conducted an RNAi screen in transgenic C. elegans (Tg worms) that overexpress human alpha-synuclein in a pan-neuronal manner. To enhance the RNAi effect in neurons, we crossed alpha-synuclein Tg worms with an RNAi-enhanced mutant eri-1 strain. We tested RNAi of 1673 genes related to nervous system or synaptic functions, and identified 10 genes that, upon knockdown, caused severe growth/motor abnormalities selectively in alpha-synuclein Tg worms. Among these were four genes (i.e. apa-2, aps-2, eps-8 and rab-7) related to the endocytic pathway, including two subunits of AP-2 complex. Consistent with the results by RNAi, crossing alpha-synuclein Tg worms with an aps-2 mutant resulted in severe growth arrest and motor dysfunction. alpha-Synuclein Tg worms displayed a decreased touch sensitivity upon RNAi of genes involved in synaptic vesicle endocytosis, and they also showed impaired neuromuscular transmission, suggesting that overexpression of alpha-synuclein caused a failure in uptake or recycling of synaptic vesicles. Furthermore, knockdown of apa-2, an AP-2 subunit, caused an accumulation of phosphorylated alpha-synuclein in neuronal cell bodies, mimicking synucleinopathy. Collectively, these findings raise a novel pathogenic link between endocytic pathway and alpha-synuclein-induced neurotoxicity in synucleinopathy.     

A Clinical Cassette Dosing Study for Evaluating the Contribution of Hepatic OATPs and CYP3A to Drug-Drug Interactions

Purpose

To demonstrate the relative importance of organic anion-transporting polypeptides (OATPs) and cytochrome P450 3A (CYP3A) in the hepatic elimination of substrate drugs.

Methods

A cocktail of subtherapeutic doses of bosentan, repaglinide, clarithromycin, darunavir, simeprevir, and midazolam (CYP3A probe) was administered orally to eight healthy volunteers. Rifampicin (OATP inhibitor; 600 mg, p.o.) and itraconazole (CYP3A inhibitor; 200 mg, i.v.) were coadministered with the cocktail in the second and third phases, respectively. Based on the extended clearance concept, in vivo β values (fraction of metabolism plus biliary excretion among all the intracellular fates of drugs including basolateral efflux) and R_dif values (ratio of diffusional uptake to active uptake) were estimated.

Results

Rifampicin increased plasma AUCs of bosentan (×3.2), repaglinide (×1.9), clarithromycin (×1.9) and simeprevir (×7.2). Itraconazole increased those of clarithromycin (×2.3), simeprevir (×2.2) and midazolam (×3.7), which had relatively small β values. The plasma AUC of bosentan (with relatively large β and small R_dif) was dominated by OATP-mediated uptake. The AUC of simeprevir was also dominated by OATP-mediated uptake because of its small R_dif value.

Conclusions

The DDI study clarified the rate-determining processes of OATP/CYP3A substrates. Our analyses provide valuable information for predicting complex drug–drug interactions involving multiple processes.

     

Foveal and Macular Thickness in a Japanese Population: The Hisayama Study

Purpose: To examine factors associated with foveal thickness (FT) and macular thickness (MT) in Japanese persons from Hisayama.

Methods: A total of 2216 healthy eyes of 1384 participants were analyzed. Each participant underwent comprehensive physical and ophthalmic examinations, the latter including optical coherence tomography (OCT). Multiple regression analysis was used to determine the relationship of various factors (race, age, sex, refractive error, axial length, diabetes mellitus, fasting plasma glucose levels, alcohol intake and smoking status) to FT (central 1-mm foveal area) and MT (central 3-mm foveal region).

Results: Results of multiple linear regression analysis indicated that age was positively associated with FT (β coefficient 0.214 μm). FT was significantly smaller in women than men (β coefficient ?9.146 μm). For both sexes, body height was positively correlated (β coefficient 0.257 μm), while refractive error and current smoking were negatively associated (β coefficients ?1910 μm and ?4.410 μm, respectively) with FT. With respect to MT, there were negative associations between age, sex (female), and refractive error (β coefficients ?0.268 μm, ?4.815 μm and ?0.699 μm, respectively). For both sexes, body height was positively correlated (β coefficient 0.227 μm), while hypertension and current smoking were negatively associated (β coefficients ?1.999 μm and ?2.758 μm, respectively) with MT.

Conclusions: Our results indicated that age, body height, refractive error, and current smoking were significantly associated with FT, whereas age, body height, refractive error, current smoking, and hypertension were significantly related to MT. Women had significantly smaller FT and MT than men.     

Evaluation of Japanese people's perception of risk information for making decisions to receive influenza and rubella vaccinations

BackgroundGenerally, vaccination uptake in Japan lags behind World Health Organization targets.ObjectiveThis study aimed to understand how risk information and advice affect intention to receive vaccinations.MethodsThis study had a within‐subjects design. An online survey based on the Health Belief Model was sent to 2501 Japanese individuals (≧20 years) to assess the intention to be vaccinated for influenza and rubella after receiving minor and severe risk information and hypothetical advice about each vaccine. Regression analysis was used to measure changes in intentions to receive each vaccination after being provided with (1) risk information about each vaccine and (2) hypothetical encouragement and discouragement to be vaccinated.Main OutcomesThe main outcomes included changes in vaccination intentions from baseline.ResultsForty‐one percent (N = 1030) of those sent the survey completed it. At baseline, 43% and 65% of the respondents intended to have influenza and rubella vaccinations, respectively. Being provided with information about severe risks and susceptibility increased the intention to have the influenza vaccination among females in their 40s. Receiving inaccurate and discouraging information from one''s mother significantly decreased the intention to have the rubella vaccination. Women 50 and older were more likely to intend not to have vaccination for rubella. Severe risk information decreased rubella vaccination intention in all age groups, except women in their 30s and 40s (p < .05).ConclusionFor both vaccinations, older individuals demonstrated vaccine hesitancy. This group requires tailored messaging to help them understand their vulnerability (to influenza) and their role in transmission (for rubella) to encourage uptake of essential vaccinations.Patient or Public ContributionMembers of the Japanese public responded to our online questionnaire on vaccination risk.     

Thermolabile polymorphism of carnitine palmitoyltransferase 2: A genetic risk factor of overall acute encephalopathy

ObjectivesAcute encephalopathy is an acute brain dysfunction after preceding infection, consisting of multiple syndromes. Some syndromes, such as acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), are severe with poor outcome, whereas others, such as clinically mild encephalitis/encephalopathy with reversible splenial lesion (MERS), are mild with favorable outcome. Previous study reported the association of the thermolabile polymorphism in Carnitine Palmitoyltransferase 2 (CPT2) gene and severe syndromes of acute encephalopathy. To further explore the pathogenetic role of CPT2 in acute encephalopathy, we conducted a case-control association study of a typical thermolabile CPT2 polymorphism, rs2229291, in 416 patients of acute encephalopathy, including both severe and mild syndromes.MethodsThe case cohort consisted of 416 patients, including AESD, MERS, and other syndromes. The control subjects were 100 healthy Japanese. rs2229291 was genotyped by Sanger sequencing. Genetic distribution was compared between the patients and controls using Cochran-Armitage trend test.ResultsMinor allele frequency of rs2229291 was significantly higher in AESD (p = 0.044), MERS (p = 0.015) and entire acute encephalopathy (p = 0.044) compared to the controls. The polymorphism showed no significant association with influenza virus, or with outcome.ConclusionsThis study provided evidence that CPT2 is a susceptibility gene for overall acute encephalopathy, including both severe and mild syndromes, and suggested that impairment of mitochondrial metabolism is common to various syndromes of acute encephalopathy.     

Preliminary Clinical Study to Evaluate the Relationship between Systemic Bone Turnover and the Microstructure of the Alveolar Bone

The objective of this study was to assess the possibility of developing a clinical minimally invasive and standardized method to evaluate the relationship between the microstructure of the jaw bone and systemic bone turnover. For this purpose, we performed standardized bone biopsy of the alveolar bone, and compared the 3D bone microstructure using micro-computed tomography (micro-CT) with bone mineral density (BMD) of the lumbar spine and biochemical markers of bone turnover. We evaluated a total of 9 samples taken from 6 patients by standardized biopsy using a trephine bur. BMD was evaluated using dual energy X-ray absorptiometry (DXA). Regarding the biochemical markers of bone turnover, serum bone-specific alkaline phosphatase (BAP) and serum osteocalcin (OC) were used as bone formation markers, and urinary cross-linked N-telopeptides of type I collagen (NTx) and urinary deoxypyridinoline (DPD) were selected as bone resorption markers. We scanned micro-CT images of these samples. Bone volume fraction (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), trabecular spacing (Tb.Spac), fractal dimension, trabecular bone pattern factor (TBPf) and node-strut (Nd.Nd/TV, TSL/TV) were measured. Regarding the correlations between the parameters of bone microstructures, TB/TV, Tb.N, fractal dimension, and node-strut seemed to be positively correlated and Tb.Spac and TBPf seemed to be negatively correlated with each other, but Tb.Th seemed to have a low correlation with other parameters. OC and/or BAP showed a significantly high correlation with many structural parameters (p < 0.05%). In conclusion, some microstructural parameters may change according to the systemic bone turnover.     

Role of the renin-angiotensin system in gynecologic cancers

Recent studies have shown an activation of the local renin-angiotensin system (RAS) in various tumor tissues, including the abundant generation of angiotensin II (Ang II) by angiotensin-converting enzyme (ACE) and the upregulation of angiotensin II type 1 receptor (AT1R) expression. Thus, considerable attention has been paid not only to the role of the RAS in cancer progression, but also to the blockade of RAS as a new approach to the treatment of human cancer. There is increasing evidence that the Ang II-AT1R pathway is involved in tumor growth, angiogenesis and metastasis in various experimental animal models, suggesting the therapeutic potential of an ACE inhibitor and AT1R blocker. In addition, specific Ang II-degrading enzymes are also expressed in tumors and play a regulatory role in tumor cell proliferation and invasion. This review focuses on the role of the RAS in the progression of gynecologic cancers, such as cervical cancer, endometrial cancer, ovarian cancer, and gestational choriocarcinoma. We present here the clinical potential of blocking the RAS as a novel and promising strategy for the treatment of gynecologic cancers.